Myopathy Induced by HMG–CoA Reductase Inhibitors in Rabbits: A Pathological, Electrophysiological, and Biochemical Study

Nakahara, Keiichi; Kuriyama, Masaru; Sonoda, Yoshito; Yoshidome, Hiroaki; Nakagawa, Hiroto; Fujiyama, Jiro; Higuchi, Itsuro; Osame, Mitsuhiro

doi:10.1006/taap.1998.8491

Cited by 102 publications

(66 citation statements)

References 29 publications

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“…For instance it has been shown that simvastatin was able to reduce ubiquinone level and mitochondrial function in human skeletal muscle [44]. Although controversial data have been reported [45][46], it has proposed that muscle cell treatment with ubiquinone can restore statininduced muscle damage [47]. Thus the observation that NADH dehydrogenase was down-regulated in the proteomic map of atorvastatin treated skeletal muscles strongly support the hypothesis of Page 18 of 47 A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 18 mitochondrial involvement [17].…”

Section: Oxidative Metabolismmentioning

confidence: 99%

Statin or fibrate chronic treatment modifies the proteomic profile of rat skeletal muscle

Camerino

Pellegrino

Brocca

et al. 2011

Biochemical Pharmacology

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Statins and fibrates can cause myopathy. To further understand the causes of the damage we performed a proteome analysis in fast-twitch skeletal muscle of rats chronically treated with different hypolipidemic drugs. The proteomic maps were obtained from extensor digitorum longus (EDL) muscles of rats treated for 2-months with 10mg/kg atorvastatin, 20mg/kg fluvastatin, 60mg/kg fenofibrate and control rats. The proteins differentially expressed were identified by mass spectrometry and further analysed by immunoblot analysis. We found a significant modification in 40 out of 417 total spots analysed in atorvastatin treated rats, 15 out of 436 total spots in fluvastatin treated rats and 21 out of 439 total spots in fenofibrate treated rats in comparison to controls. All treatments induced a general tendency to a down-regulation of protein expression; in particular, atorvastatin affected the protein pattern more extensively with respect to the other treatments.Energy production systems, both oxidative and glycolytic enzymes and creatine kinase, were downregulated following atorvastatin administration, whereas fenofibrate determined mostly alterations in glycolytic enzymes and creatine kinase, oxidative enzymes being relatively spared. Additionally, all treatments resulted in some modifications of proteins involved in cellular defenses against oxidative stress, such as heat shock proteins, and of myofibrillar proteins. These results were confirmed by immunoblot analysis. In conclusions, the proteomic analysis showed that either statin or fibrate administration can modify the expression of proteins essential for skeletal muscle function suggesting potential mechanisms for statin myopathy.

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Section: Oxidative Metabolismmentioning

confidence: 99%

Statin or fibrate chronic treatment modifies the proteomic profile of rat skeletal muscle

Camerino

Pellegrino

Brocca

et al. 2011

Biochemical Pharmacology

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“…Although myotonic potentials have been described in some drug-related myopathies, they are rarely reported in CLAM. Though there are a few experimental myotonic myopathy associated with statin in rabbits [4][5][6] , there was only one single report describing 5 patients with this finding in humans 7 .…”

mentioning

confidence: 99%

Myotonic potentials in statin-induced rhabdomyolysis

Almeida

Lissa

Melo

2008

Arq. Neuro-Psiquiatr.

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Lipid lowering drugs are used worldwide to control dyslipidemias. The muscle disorder associated with them are coined cholesterol-lowering agents myopathy (CLAM) 1 . The annual incidence of rhabdomyolysis in patients taking statins is 3.4 per 100000 persons 2 . Between 1987 and 2001 there were 42 deaths +related to statin-induced rhabdomyolysis, resulting in a mortality rate of 0.15 per million of prescriptions 3 . Although myotonic potentials have been described in some drug-related myopathies, they are rarely reported in CLAM. Though there are a few experimental myotonic myopathy associated with statin in rabbits 4-6 , there was only one single report describing 5 patients with this finding in humans 7 .We report a patient with statin-related rhabdomyolysis and profuse myotonic potentials in the needle EMG with clinical and electrophysiological recovery shortly after the statin interruption. CaSeA 68 year-old Asian Brazilian woman was admitted with progressive painless weakness for one week, started on the proximal muscles of the four limbs and neck flexors with rapid progression to inability to walk and elevate the limbs. Urine was redbrown in color. Thirty days before the admission she was put on simvastatin due to hypercholesterolemia. Other medication she was taking was enalapril for mild hypertension. There was no personal or family history of myopathy. On neurological examination, abnormal findings were grade 2 (MRC) strength in the proximal lower limb muscles and grade 3 in the proximal upper limb muscles, grade 4 in the distal muscles and hypoactive deep tendon reflexes. No clinical myotonia was detected.A complete blood count, electrolytes, creatinine, glucose, TSH, and free T4 were all normals. Myoglobin was detected in the urine. CPK was 22.260 U/l on the admission day and 55.000 U/l on the third day. AST and ALT were 790 and 750 U/l, respectively. The nerve conduction studies perfomed in both arms and legs showed normal results in the median, ulnar, superficial radial, tibial, peroneal, superficial peroneal and sural nerves bilaterally. The F wave latencies were normal in the median, ulnar, fibular and tibial nerves bilaterally. The needle EMG perfomed with disposable monopolar needle in cervical paraspinal, supraspinatus, deltoid, triceps, abdutor pollicis brevis and first dorsal interosseus in the upper right limb and tibialis anterior, gastrocnemius, vastus lateralis and iliopsoas in the right lower limb showed rare positive sharp waves and fibrillations in the right supraspinatus muscle, as well as a few small amplitude and short duration (SASD) motor unit potentials (MUP) in the right iliopsoas muscle. On the other hand, the needle study showed profuse amount of myotonic potentials in deltoid, supraspinatus, iliopsoas and cervical paraspinal muscles on the right side (Fig 1).Simvastatin was stopped and vigorous hydration was started to prevent acute renal failure. She was discharged two weeks later with normal strength, renal function and CPK levels. A second needle EMG performed 30 days after...

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“…In rabbits administered with simvastatin by gavage for 4 weeks, the pathological findings are muscle fiber necrosis and degeneration by light microscopy and disruption and hypercontraction of myofibrils by electron microscopy [34]. For 15-16 days of daily administration of simvastatin to rats the development of muscle fiber necrosis occurs in 17 particular individual muscles (extensor digitorum longus, gastrocnemius, biceps femoris, semitendinosus, semimembranosus, tibialis cranialis, vastus medialis, supraspinatus, triceps brachii caput longum, triceps brachii caput laterale, biceps brachii, extensor carpi radialis longus, trapezius, longissimus lumborum, diaphragm, abdominal peritoneal, panniculus carnosus from skin) [35] indicating a communion of the effect.…”

Section: Toxicity Of Simvastatinmentioning

confidence: 99%

“…In rabbits administered chronically with simvastatin, skeletal muscle mitochondrial swelling and a decrease in skeletal muscle CoQ are observed [34]. Simvastatin administered to dogs for 3 weeks significantly decreases the myocardial level of CoQ and causes worsening of the myocardial mitochondrial respiration [64].…”

Section: Effects Of Simvastatin On Mitochondrial Function In Vivomentioning

confidence: 99%

“…Human skeletal muscle Mitochondrial DNA fragmentation [62] Rat skeletal muscle Changes in mitochondrial morphology [35] Rabbit skeletal muscle Mitochondrial swelling and a decrease in CoQ [34] Dog myocardium Decrease in CoQ and mitochondrial respiration [64] Rat lens Decrease in CoQ [38] Mouse liver and heart mitochondria Decrease in CoQ, increase in lipid peroxidation products [58] inhibitor of calcineurin and mitochondrial permeability transition (MPT). At 60 µM, simvastatin induced the necrosis preceded by a threefold increase in cytosolic free Ca 2+ concentration and a significant decrease in both respiration rate and mitochondrial membrane potential.…”

Section: Object Effects Of Simvastatin Refsmentioning

confidence: 99%

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Molecular mechanisms of toxicity of simvastatin, widely used cholesterol-lowering drug. A review

Kaminsky

Kosenko

2010

Open Medicine

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AbstractStatins are widely used and well tolerated cholesterol-lowering drugs, and when used for therapy purposes reduce morbidity and mortality from coronary heart disease. Simvastatin is one of nine known statins, specific inhibitors of hepatic enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the rate-limiting step of cholesterol biosynthesis, and is believed to reduce plasma cholesterol levels by decreasing the activity of this enzyme. Statin drugs represent the major improvement in the treatment of hypercholesterolemia that constitutes the main origin of atherosclerosis, leading to coronary heart disease. Although statins are generally safe, minor and severe adverse reactions are well known complications of statin use. Adverse events associated with simvastatin therapy are uncommon, but potentially serious. In this review some details about statins including their adverse effects in humans and animals, the effects of simvastatin on various intracellular and mitochondrial processes, and molecular mechanisms underlying simvastatin cytotoxicity are discussed.

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Myopathy Induced by HMG–CoA Reductase Inhibitors in Rabbits: A Pathological, Electrophysiological, and Biochemical Study

Cited by 102 publications

References 29 publications

Statin or fibrate chronic treatment modifies the proteomic profile of rat skeletal muscle

Statin or fibrate chronic treatment modifies the proteomic profile of rat skeletal muscle

Myotonic potentials in statin-induced rhabdomyolysis

Molecular mechanisms of toxicity of simvastatin, widely used cholesterol-lowering drug. A review

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